Learning processes allow organisms (including humans) to adapt their behavior to changes in the environment, and are thus crucial for survival. However, learning does not take place in a vacuum. Indeed, most learning experiences occur within complex environments composed of visual, auditory, olfactory, and tactile stimuli. To successfully learn about biologically significant events (e.g., the presence of food or prey) that occur within particular environments, animals must first combine individual features of the environment into an integrated memory, or "context" representation. Contemporary research suggests that this type of learning occurs within cortico-hippocampal networks in the brain. However, the exact pathways and individual functions of particular regions essential for learning about contexts have not been fully resolved. The overarching hypothesis of this proposal is that the restrosplenial cortex (RSP) is essential for forming integrated context representations, and that the postrhinal cortex (POR) is essential for updating these memories. This proposal addresses unanswered questions about the neural substrates of contextual fear learning (Specific Aim 1). It also addresses the functional role of RSP and POR in the recovery of fear to a previously extinguished fear cue. Fear extinction is context specific, and recovery can result either from re-experiencing the aversive event (i.e., reinstatement;Specific Aim 2) or when a significant amount of time has passed since fear extinction occurred (i.e., spontaneous recovery;Specific Aim 3). In all studies, RSP and POR will be temporally inactivated using a new and innovative technique: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This temporary inactivation will allow for isolation of the role of these regions during encoding and/or retrieval processes. In sum, this proposal examines the role of RSP and POR in context learning and fear extinction, two processes that are important in the development and subsequent treatment of several mental illnesses in humans (e.g., post-traumatic stress disorder: PTSD;anxiety related disorders, phobias). Further, the RSP is known to be compromised in human disorders such as schizophrenia and Alzheimer's disease. Therefore, investigating the role of RSP and POR, during both fear learning and fear extinction, could prove to be especially informative to clinical practice in humans.

Public Health Relevance

This project has the potential to produce novel insights into the neural substrates of learning and memory, particularly contextual fear learning and fear extinction. By investigating the neural substrates of context learning and fear extinction (the animal model of cue-exposure therapy in humans), this work may lead to a deeper understanding of cue-exposure therapy, a commonly employed therapy used to treat a variety of human disorders (e.g., post-traumatic stress disorder: PTSD, anxiety related disorders, phobias). Further, by investigating a brain region (the retrosplenial cortex) that is known to be compromised in human disorders such as schizophrenia and Alzheimer's disease, the proposed experiments may inform clinical practice and treatments for these disorders.